Acute Porphyria Drugs

Acute Porphyria Drug Database

N05AF05 - Zuclopenthixol
Propably not porphyrinogenic
PNP
Rationale
Zuclopenthixol is a substrate of CYP2D6 and CYP3A4. It is not listed as inducer or inhibitor of any major CYP enzymes. Risk for gastrointestinal adverse events in the form of obstipation, vomiting, dyspepsia and diarrhoea motivates vigilance against insufficient intake of food, especially of carbohydrate.
Therapeutic characteristics
Zuclopenthixol is indicated for the treatment of schizophrenia and other psychoses. Common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are obstipation, vomiting, dyspepsia and diarrhoea. Another common side effect is myalgia. Less common side effects are abdominal pain and nausea. Abrupt discontinuation of zuclopenthixol may be accompanied by withdrawal symptoms. The most common symptoms are nausea, vomiting, anorexia, diarrhoea, rhinorrhoea, sweating, myalgias, paraesthesias, insomnia, restlessness, anxiety, and agitation. Patients may also experience vertigo, alternate feelings of warmth and coldness, and tremor. Symptoms generally begin within 1 to 4 days of withdrawal and abate within 7 to 14 days (SPC).
Metabolism and pharmakokinetics
Zuclopenthixol is metabolised by CYP2D6 (Dahl 2002 and SPC) to inactive metabolites (Norsk legemiddelhåndbok). In vitro data indicates that zuclopenthixol is metabolised by CYP2D6 and CYP3A4 (Davies 2010). A therapeutic drug monitoring study also suggested the same (Davies 2010). Zuclopenthixol is not listed as an inducer or inhibitor or any major CYP enzymes (Isoherranen 2009 and Pelkonen 2008).
Published experience
Zuclopenthixol is listed as unsafe because it has been shown to be porphyrinogenic in animals or in vitro systems (Moore 1997).

References

  1. Scientific articles
  2. Cascorbi I. Genetic basis of toxic reactions to drugs and chemicals. Toxicol Lett. 2006 Mar 15;162(1):16-28 #2651
  3. Dahl ML. Cytochrome p450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing? Clin Pharmacokinet. 2002;41(7):453-70. PMID 12083975. #2652
  4. Davies SJ, Westin AA, et al. Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies. Acta Psychiatr Scand. 2010 Dec;122(6):444-53. PMID 20946203. #4670
  5. Isoherranen N, Hachad H, et al. Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: literature evaluation based on the metabolism and transport drug interaction database. Chem Res Toxicol. 2009 Feb;22(2):294-8. #1005
  6. Moore MR, Hift RJ. Drugs in the acute porphyrias--toxicogenetic diseases. Cell Mol Biol (Noisy-le-grand). 1997 Feb;43(1):89-94. PMID 9074793. #1110
  7. Pelkonen O, Turpeinen M, et al. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol. 2008 Oct;82(10):667-715. PMID 18618097. #4347
  8. Drug reference publications
  9. Norsk legemiddelhåndbok. Zuklopentiksol #2654
  10. Summary of Product Characteristics
  11. Norwegian medicines agency. Summary of Product Characteristics (SPC). Zuklopentiksol. #2655
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